rs61752334
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_014780.5(CUL7):āc.3041T>Gā(p.Leu1014Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000169 in 1,612,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (ā ā ).
Frequency
Consequence
NM_014780.5 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CUL7 | NM_014780.5 | c.3041T>G | p.Leu1014Arg | missense_variant, splice_region_variant | 16/26 | ENST00000265348.9 | |
LOC124901318 | XR_007059581.1 | n.1915A>C | non_coding_transcript_exon_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CUL7 | ENST00000265348.9 | c.3041T>G | p.Leu1014Arg | missense_variant, splice_region_variant | 16/26 | 1 | NM_014780.5 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000986 AC: 15AN: 152088Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000163 AC: 41AN: 251280Hom.: 0 AF XY: 0.000177 AC XY: 24AN XY: 135792
GnomAD4 exome AF: 0.000177 AC: 258AN: 1460766Hom.: 0 Cov.: 31 AF XY: 0.000180 AC XY: 131AN XY: 726442
GnomAD4 genome ? AF: 0.0000986 AC: 15AN: 152088Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10AN XY: 74270
ClinVar
Submissions by phenotype
not provided Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Nov 30, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 07, 2015 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 24, 2023 | This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1014 of the CUL7 protein (p.Leu1014Arg). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 194657). This missense change has been observed in individual(s) with 3-M syndrome (PMID: 16142236, 19225462, 21396581; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs61752334, gnomAD 0.03%). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 28, 2022 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported as pathogenic in ClinVar but additional evidence is not available (ClinVar SCV000263029.3, SCV000226508.5; ClinVar); This variant is associated with the following publications: (PMID: 16142236, 19225462, 34426522) - |
3M syndrome 1 Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Jun 08, 2023 | PM3_strong, PM2, PP3 - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Inherited Metabolic Diseases, Research centre for medical genetics | Apr 01, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | Jul 24, 2024 | This variant is interpreted as likely pathogenic for 3M syndrome 1, based on the following ACMG criteria: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3_moderate; REVEL score 0.849). For recessive disorders, detected in trans with a pathogenic variant (PM3_strong; family 22 in PMID:16142236 and family 44 in PMID:19225462). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Dec 12, 2019 | This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3. This variant was detected in homozygous state. - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 10, 2014 | - - |
3-M syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 22, 2022 | Variant summary: CUL7 c.3041T>G (p.Leu1014Arg) results in a non-conservative amino acid change located in the Cullin, N-terminal domain (IPR001373) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00016 in 251280 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in CUL7 causing Three M Syndrome 1 (0.00016 vs 0.0011), allowing no conclusion about variant significance. c.3041T>G has been reported in the literature in multiple individuals affected with Three M Syndrome (Huber_2005, Huber_2009), including in a family with compound heterozygous individuals with a truncating variant. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and six classified it as pathogenic/likely pathogenic (one as uncertain significance). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at